The BMP Inhibitor Coco Reactivates Breast Cancer Cells at Lung Metastatic Sites

The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-β ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung, but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific antimetastatic signals in order to undergo reactivation. [Display omitted] ► The secreted BMP inhibitor Coco mediates breast cancer colonization of the lung ► Coco induces exit from dormancy and reactivation by blocking paracrine BMP signaling ► BMP signaling inhibits cancer stem cell traits and lung colonization ► Coco-dependent gene expression signatures predict relapse to the lung in patients BMP signaling in the lung limits self-renewal of extravasated breast cancer cells, but expression of a BMP inhibitor by a subset of cancer cells enables metastatic colonization and triggers a cancer stem-cell like program. Understanding organ-specific signals that limit metastatic colonization may provide inroads for the treatment of metastatic disease.